Development of a simple clinical score to prioritize detection of severe α-1 antitrypsin deficiency with the PiZZ genotype.

PURPOSE: α-1 antitrypsin deficiency is caused primarily by the PiZZ genotype in SERPINA1 and remains underdiagnosed, despite its association with severe lung and liver diseases. We aimed to develop and validate a clinical score using electronic health record data to identify individuals who are more likely to have the PiZZ genotype.

METHODS

In the UK Biobank (UKB; N = 277,082), we developed the clinical score using logistic regression with variable selection based on medical conditions and anthropometric measurements. We evaluated its performance against random screening and targeted screening based on individual medical conditions in an independent UKB test data set (N = 69,272) and the National Institutes of Health All of Us Research Program (N = 162,198).

RESULTS

The optimized clinical score included chronic obstructive pulmonary disease, bronchiectasis, cirrhosis, and height. In the UKB test data set and All of Us Research Program, the score outperformed any single phenotype in identifying the PiZZ genotype. Targeting individuals in the top 0.5% of the score increased screening efficiency by >95% compared with random screening and outperformed all medical condition-based screening strategies.

CONCLUSION

Using readily available electronic health record data, the clinical score represents a starting point that may improve targeted case-finding and optimize the allocation of diagnostic resources for α-1 antitrypsin deficiency.